Bone is composed of a protein matrix into which an inorganic mineral component is incorporated. Bone resorption requires both the dissolution of the inorganic mineral component as well as proteolytic degradation of the protein matrix. Cysteine proteases are thought to be involved in bone resorption since prototypic inhibitors of cysteine proteases can prevent osteoclast mediated bone resorbtion using in vitro and in vivo models. A novel cysteine protease, termed cathepsin K, has been identified from rabbit (Tezuka, K-i., Tezuka, Y., Maejima, A., Sato, T., Nemoto, K., Kamioka, H., Hakeda, Y., and Kumegawa, M. (1994) J. Biol. Chem. 269, 1106-1109), human (Shi, G-P., Chapman, H. A., Bhairi, S. M., DeLeeuw, C., Reddy, V. Y., and Weiss, S. J. (1995) FEBS Lett. 357, 129-134; Bromme, D. and Okamoto, K. (1995) Biol. Chem. Hoppe-Seyler 376, 379-384; Li, Y. P., Alexander, M. B., Wucherpfennis, A. L., Chen, W., Yelick, P., and Stashenko, P. (1994) Mol. Biol. Cell5, 335a; Inaoka, T., Bilbe, G., Ishibashi, O., Tezuka, K-i., Kamegawa, M., and Kokubo, T. (1995) Biochem. Biophys. Res. Commun. 206, 89-96), and murine tissues (Rantakokko, J., Aro, H. T., Savontaus, M., and Vuorio, E. (1996) FEBS Letters393, 307-313). Cathepsin K was found to be abundantly and selectively expressed in osteoclasts (Drake, F., et al, J. Biol. Chem. 271:12511-12516, 1996). Other closely related members of the cysteine protease family (cathepsins S, L, B) are either very low or absent in osteoclasts. The high level, localized expression of cathepsin K in osteoclasts strongly suggests a role in bone resorption. Selective inhibitors of human cathepsin K could be useful in the treatment of a number of diseases involving bone loss, such as osteoporosis, periodontal disease, arthritis, and Paget's disease. Assays to evaluate potential cathepsin K inhibitors requires large amounts of purified enzyme which can be achieved through the cloning, expression and purification of recombinant molecules. Characterization and development of inhibitors of human cathepsin K for prevention of bone resorption utilizes both in vitro and in vivo animal model systems, particularly from rat. The cloning and expression of the rat cathepsin K ortholog is of significant value in assessing species differences in pharmacological activity of inhibitors between rat and human cathepsin K, and for identifying those compounds that possess inhibitory activity against either rat cathepsin K, human cathepsin K, or both.
This indicates that these cysteine proteases have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further members of cysteine proteases family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, osteoporosis, periodonatal disease, arthritis, cancer, tumor metastasis, and Paget's disease.